Personality disorders in individuals with functional seizures: a systematic review

Functional seizures (FS) are classified as conversion disorders in the DSM-5 and dissociative disorders in the ICD-11, showing a multifactorial psychopathology with various psychiatric comorbidities, such as depression and anxiety. Several studies have found a correlation between FS and personality disorders, mainly those in cluster B. Within this cluster, borderline personality disorder (BPD) or borderline personality traits are the most prevalent in FS. Emotion dysregulation is a hallmark of BPD and is commonly reported in individuals with FS. Cluster C personality disorders, such as avoidant or obsessive-compulsive disorders, have also been reported in FS. In this review, we aim to evaluate the relationship between FS and personality disorders. Assessing personality disorders in the context of FS is relevant for determining the most appropriate intervention. Cognitive-behavioral therapy (CBT) is considered the first-line approach to treating FS. Among various CBT strategies, dialectical behavior therapy, which specifically targets emotion dysregulation, may be helpful for individuals with BPD. Future research should assess the advantages of systematically evaluating personality disorders in FS to address specific treatment planning and evaluate its effectiveness on seizure recurrence, psychological comorbidities, and quality of life. Systematic review registration https://www.crd.york.ac.uk/PROSPEROFILES/509286_STRATEGY_20240203.pdf, identifier CRD42024509286.


Introduction
Psychogenic nonepileptic seizures, also known as functional seizures (FS), are defined as paroxysmal altered motor, sensory, autonomic, and/or cognitive signs and symptoms that resemble an epileptic seizure but are not caused by ictal epileptiform activity (1).FS are classified as a subgroup of conversion disorders (functional neurological symptom disorder) according to the DSM-5 (2) or as a dissociative neurological symptom disorder with non-epileptic seizures in the ICD-11 (3).The diagnosis reaches the highest certainty level recording a typical event at video-EEG (1).FS are frequently mistaken for epilepsy, delaying the correct diagnosis by an average of 7 years (4,5).The misdiagnosis leads to inappropriate treatment, with a significant impact on quality of life, morbidity, and healthcare costs (1,6).In the general population, FS have an estimated incidence of 1.4-4.9/100,000/yearand a prevalence between 2 and 33 cases per 100,000 (7).Several theoretical models have been proposed to explain FS development (8,9).Initially interpreted as a dissociative phenomenon, FS have been derived from a breakdown in psychological integration in response to intense stress or emotion, appearing as a sensorimotor flashback when traumatic dissociated material comes into consciousness (7).Accordingly, the prevalence of traumatic life events varied from 44% to 100% in FS.In particular, sexual abuse is three times more common among FS individuals, ranging from 6% to 85% (7,10).In addition, childhood emotional neglect, defined as the carelessness of the affectional needs of a child, demonstrated a strong association with FS.Noteworthy, not all individuals reported past exposure to traumatizing events, configuring trauma as neither a necessary nor sufficient condition.Subsequent theory interpreted FS as avoidant/ defensive reaction in response to overwhelming situations or traumatic experiences in individuals with low capacity for coping stressful life events (7).A variant of this model interprets FS as a physical component of emotional states not recognized or misinterpreted by individuals due to their inability to identify and/ or name emotions (i.e., alexithymia) seen as unacceptable.A further model explains FS as learned behavior maintained by positive or negative reinforcement thanks to intrinsic/extrinsic benefits, like reducing anxiety, relieving duties, or getting attention (8).Recently, "integrative cognitive model" conceptualized FS as behavioral paroxysms resulting from automatic activation of learnt mental representations, defined "seizure scaffold" (7).In detail, an attack's semiology depends on the content of the scaffold, acquired from internal (as direct symptom experience) or external (as attendance of symptom) sources (11).
FS comprehend concomitant heterogeneous psychiatric disorders, ranging from 53 to 100% (12, 13), and being able to represent predisposing/precipitating factor, underlying etiology, or consequence (14).Depression demonstrated a prevalence rate varying between 8.9% and 100% (13).Suicide risk has been shown to be greater in people with FS compared to the general population (15).Furthermore, the prevalence of anxiety disorders varied between 4.5% and 70%, including panic disorder and generalized anxiety disorder.FS individuals meeting the criteria for post-traumatic stress disorder (PTSD) ranged from 7% to 100% (13).Personality disorders (PDs) demonstrated a high prevalence among people with FS, up to 75% in some reports (13).Within PDs, cluster B, mainly borderline PD (BPD), appears as the most common personality phenotype (15,16).Interestingly, FS and BPD seem to have some mutually common aspects, sharing a history of traumatic experiences, depression, and PTSD (17).Moreover, emotional dysregulation, considered a BPD hallmark, is commonly described in FS (18).Likewise, cluster C PDs, such as avoidant or obsessive-compulsive, have also been reported in FS (9).Assessment of PDs in the context of FS could be particularly relevant in choosing therapeutic intervention.
As widely recognized, psychotherapy, including cognitivebehavioral therapy (CBT), is the most commonly used approach to treating FS (19).Dialectical-behavior therapy (DBT) is a form of CBT specifically developed for BPD targeting emotion dysregulation and has proved efficacy in FS (9, 20).Therefore, investigating BPD in FS individuals could be relevant to tailoring a therapeutic approach.Nevertheless, few studies evaluated the frequency of PDs in individuals with FS using DSM IV/V criteria.Moreover, systematic analysis of PD clusters found in FS is currently unavailable (13).
This systematic review aims to assess the following in the adult FS population: I) prevalence of PDs diagnosed according to DSM-IV/V or ICD-10/11; II) frequency of clusters A, B, and C in studies evaluating personality phenotypes; and III) PDs and their cluster rates compared to individuals with epilepsy across studies considering both groups.Databases PubMed, OVID Medline, and PsycINFO were searched, including the following terms:
The * indicates that any combination of letters after the initial string was accepted.All search words were not case-sensitive.
This search, performed on 03 February 2024, returned 70 articles on PubMED, 19 on OVID Medline, and 82 on PsycINFO (Figure 1).
After the removal of duplicated articles, the combined searches produced 123 articles.No further papers were identified after searching the reference list of the included articles.

Papers' assessment for eligibility
Each qualifying article underwent a thorough evaluation based on the following inclusion and exclusion criteria: availability of the full text, written in English, primary research article (case reports with ≥5 individuals were included), related to humans with FS, studies enrolling individuals aged ≥18 years, and PDs diagnosed according to DSM-IV/V or ICD-10/11.Restrictions on the publication's year were not applied.Papers regarding PDs in infants or adolescents were not considered for this review because our aims included the frequency of all PDs, and the diagnosis of antisocial PD requires at least an age of 18 years in accordance with DSM-V criteria (2).
Three independent reviewers (IM, IS, and FF) assessed each article by title and abstract/full text to determine eligibility, comparing their results.Any discrepancies were resolved through consensus among the review team (IM, IS, FF, LM, and AG).

Data extraction
For each article, the following data were extracted: study setting; study population and participants' demographics and baseline characteristics; study design; year of publication; main outcome (frequency of PDs in individuals with FS); secondary outcomes (frequency of any PD phenotype in people with FS and, where available, in those with epilepsy); and information for risk of bias assessment.Three people independently extracted the data.Any disagreements were resolved by reaching a consensus within the review team.

Risk of bias
Two sources of bias were considered: inclusion bias and reporting bias in the included studies.To mitigate inclusion bias, each article was assessed by three independent and blinded reviewers.Any discrepancies between reviewers were resolved by reaching a consensus within the three-person review team.After the included articles were selected, the list was assessed by an additional reviewer (AG), and any problematic articles were thoroughly discussed within the team.We also rated each article according to the modified Newcastle-Ottawa Scale (NOS) for cross-sectional studies (22).

Statistical analysis (meta-analysis)
For articles that compared the prevalence of PDs and their relative clusters between FS and epileptic seizure groups, a meta-analysis was conducted using Cochrane's Review Manager Web tool (RevMan Web) (https://revman.cochrane.org)(23).As the considered variables are dichotomous outcomes, the Mantel-Haenszel method was used to provide the odds ratio (OR) along with its 95% confidence interval (CI) pooled in a forest plot.Heterogeneity across the analyzed studies was evaluated through the Cochrane Q test (c 2 test) and the I-squared index (I 2 ).A p-value of <0.05 was considered statistically significant.Publication bias was assessed using funnel plots.

Study selection
As reported in Figure 1, out of the 123 articles reviewed, 13 were excluded due to full-text unavailability, 6 articles were not in English, 42 were not classified as primary research articles, 8 articles regarded individuals with age <18 years, 34 had not been diagnosed with PDs according to DSM-IV/V or ICD-10/11, and 6 articles were not related to FS individuals.

Features of the included studies
Table 1 summarizes the clinical characteristics of the enrolled individuals, the edition of the DSM or ICD used for PD diagnosis, the methods used for personality assessment, and the main results of all 14 studies included.In all papers included, participants have no intellectual disability, comorbidity, or other relevant conditions, such as epilepsy or drug abuse.Noteworthily, individuals with FS alone were considered for analysis.The sample size varied from 20 to 111 across studies.The age of FS participants ranged from 18 years to 65 years (mean age: 34.9).Concordantly to the literature, the female sex is preponderant across studies, reaching 65% of the study population.In 13/14 studies (17,(24)(25)(26)(27)(28)(29)(30)(31)(33)(34)(35)(36), the FS diagnosis required the recording of typical events on video-EEG, reaching the "documented" level in accordance with the latest diagnostic criteria (1).In one study (32), FS were determined according to the criteria of the Nonepileptic Seizures Task Force of the International League Against Epilepsy (ILAE), including individuals with diagnostic levels indicated as "probable," "clinically established," and "documented" (1).Groups used as FS comparisons were not homogenous among the included studies.In detail, 5/14 studies enrolled people with epilepsy (17,28,31,33,34), 2/14 individuals with FS plus epilepsy (29,32), and 1/14 individuals with a diagnosis of a functional disorder different from FS (35); in two cases, individuals with FS and individuals with epilepsy were evaluated in comparison to healthy subjects (30) and people with FS plus epilepsy (36), respectively.

Discussion
This systematic review illustrates that PDs represent a notable comorbidity in the FS population.When analyzing personality phenotypes, cluster B is the most common PD in FS, in accordance with previous literature data (9, 16).Although at inferior rates, cluster C and, even less, cluster A have been also attested.Among all PD phenotypes, BPD represents the most common diagnosis in FS, followed at an inferior rate by avoidant PD.In comparison to people with epilepsy, our meta-analysis demonstrated in FS individuals an increased risk of having concomitant PD, particularly those belonging to cluster B. At the same time, clusters A and C appear less likely to occur in people with FS than in those with epilepsy.
In the literature, the association between FS and PDs is well recognized (13,16).A previous systematic review documented a PDs' rate between 5.4% and 74.3%, while in an earlier work this comorbidity varied from 10% to 86% in FS (16).In our analysis, the prevalence of PDs in FS falls subtly higher, ranging from 18% to 87%.Our slightly greater rate is likely due to mandatory criteria in including exclusively studies diagnosing PD in accordance with DSM-IV/V or ICD-10/11.Nonetheless, a wide disparity in PDs prevalence in FS population has been demonstrated among studies.In a previous review, this difference was attributed to a higher rate of PDs in individuals with a longer duration of FS (16).We did not confirm this trend in our work.It is not known whether differences in FS clinical semiology (such as motor and non-motor manifestations) or levels of dissociation could explain this disparity.Since not all studies included in the present review assessed these features, we were unable to conduct such an analysis.Cluster B PDs, particularly BPD, have been widely demonstrated as the most prevalent personality phenotype in FS (16).Our analysis confirmed BPD as the most frequent PD in FS, regarding more than half of this population.Other cluster B PDs have a lower frequency.In particular, although histrionic PD shares some traits with BPD, its frequency appears lower than that expected in FS, with a prevalence not exceeding 20%.Some reports describe cluster C subtypes of personality in FS.According to our data, cluster C PDs, despite their prevalence can reach up to 75.9% in FS, proved a greater association to epilepsy.
Similarly, a previous study reported cluster C more frequently in people with epilepsy than in those with FS (37).BPD combines marked impulsivity, interpersonal relationships, self-image, and affects instability, consisting of rapidly shifts between extremely positive idealization and extremely negative devaluation about self and others (2, 20).The hallmark of BPD is emotional dysregulation, reflecting an inability to respond to and manage emotional transitions (16,38).Notably, people with FS frequently exhibit emotional dysregulation and instability in interpersonal relationships (9, 16, 18).Additionally, individuals with BPD may commonly experience childhood sexual/emotional abuse or neglect and have higher rates of concurrent psychiatric disorders, such as depression or PTSD (20).Moreover, dissociative symptoms are included among the diagnostic criteria for BPD and may represent a psychological mechanism underlying FS development (7,20).Likewise, the similarity between these conditions also includes anger problems, hostile coping styles and somatoform disorder in comorbidity.In this context, BPD might be interpreted as a predisposing etiological factor for FS (30).Interpreting psychiatric disorders in FS as mere comorbidities could be misleading (12).The high heterogeneity in FS clinical and psychiatric manifestations likely reflects the wide range of underlying psychopathologies (30).
Conversely, psychiatric comorbidities might contribute to poor outcomes in FS, acting as perpetuating factors (6).
Regardless of their relationship, the identification of psychiatric disorders in FS, especially PDs, significantly impacts treatment choice.Currently, psychotherapy is the first-line therapy for both FS and BPD (19, 20).CBT has been widely demonstrated to reduce attack frequency and improve quality of life in individuals with FS (19, 26, 39).To date, two CBT approaches for FS have been evaluated through randomized controlled trials.The CBT developed by Goldstein targets factors involved in the development and maintenance of attacks, interpreting FS as dissociative responses.The CBT model reported by LaFrance promotes behavior and selfcontrol, addressing both seizures and comorbidities (19).Among the psychotherapies available for BPD, DBT was developed in accordance with Linehan's biosocial theory, which conceptualizes BPD as a pervasive dysregulation disturbance with great emotional vulnerability and a deficient ability to modulate emotions (40).DBT includes skill modules such as mindfulness, interpersonal effectiveness, emotion regulation, and distress tolerance (20, 41).In this regard, mindfulness-based therapy has shown efficacy in FS.As mentioned above, individuals with FS could be overwhelmed by their emotions, becoming detached from them as an adaptive strategy.Mindfulness increases awareness of feelings and reinforces attention to body symptoms and their misattribution (42).In this light,  characterizing concomitant psychiatric disorders allows for the individualization of treatment for FS.As mentioned above, individuals with FS may exhibit various psychopathologies, such as a dissociative response to a previous traumatic life event, a maladaptive response to overwhelming situations, or the automatic activation of learned mental representations.As expected, different etiopathologies and underlying defense mechanisms have been demonstrated to influence treatment.However, psychotherapy for FS tailored to concomitant psychiatric disorders has not yet been thoroughly investigated.
The present review has some limitations.The main limitation is the small FS sample size in each included study.Nevertheless, FS diagnosis appears quite homogeneous across studies, reaching the "documented" level in almost all cases (1).Moreover, half of the included studies evaluated the prevalence of each PD subtype, further restricting the data analysis.Additionally, the comparison groups to FS are sufficiently heterogeneous, comprising healthy subjects, people with epilepsy, and individuals with FS plus epilepsy.The epilepsy population was the most numerically represented across the included studies, allowing for a meta-analysis.
In conclusion, PDs have been shown to be a common comorbidity in FS.Cluster B, especially BPD, demonstrated a high prevalence in individuals with FS.Evaluating the presence of PDs, particularly BPD, may have relevance in personalizing FS treatment.Psychotherapy tailored to concomitant psychiatric disorders could be more effective in reducing the recurrence of attacks and improving quality of life.Systematic investigation of therapeutic approaches structured around psychiatric comorbidity is currently not available (39).Further studies are needed to clarify the potential benefits of selecting psychotherapy based on the psychiatric comorbidity of an individual, especially PDs.

FIGURE 2
FIGURE 2Meta-analysis of eligible studies comparing PDs between FS individuals and the epilepsy population (ES).

FIGURE 3
FIGURE 3Meta-analysis of eligible studies comparing Cluster B PDs between FS individuals and the epilepsy population (ES).

FIGURE 4 Meta
FIGURE 4Meta-analysis of eligible studies comparing Cluster A PDs between FS individuals and the epilepsy population (ES).

FIGURE 5
FIGURE 5Meta-analysis of eligible studies comparing Cluster C PDs between FS individuals and the epilepsy population (ES).

TABLE 1
Characteristics and results of the included studies.Quality assessment of included articles through the modified Newcastle-Ottawa Scale for cross-sectional studies.
a A maximum of 5 stars can be awarded for the selection.b A maximum of 2 stars can be awarded for comparability.c A maximum of 3 stars can be awarded for the outcome.